Alzheimer's Disease: Slowing Down the Course

Mary M. Barna, PharmD, and Francis L. Hughes, PharmD, BCPS

Published Online: Sunday, March 1, 2009

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Drs. Barna and Hughes are both clinical assistant professors in the Department
of Pharmacy Practice and Administration at Ernest Mario School of Pharmacy,
Rutgers—The State University of New Jersey in Piscataway, New Jersey.

Alzheimer's disease (AD) is an
incurable, irreversible, and progressive
neurologic disease and
is the most common cause of dementia.
According to the US Census 2000,
it was estimated that nearly 4.5 million
Americans had AD. As the baby
boom generation of the United States
ages, the prevalence of this debilitating
disease, primarily associated with
advancing age, is projected to triple to
affect an estimated 13.2 million individuals
by 2050.1 The National Center
for Health Statistics data indicate that
AD surpassed diabetes to become the
sixth leading cause of death in the
United States in 2006, with an estimated
72,914 Americans succumbing
to this disease.2 The growing incidence
of AD in the United States represents
a mounting public health problem and
mandates that clinicians have a strong
understanding of both the disease and
various treatment modalities.

Pathophysiology

The current cause of AD is not fully
known, but the amyloid cascade hypothesis
is the leading hypothesis describing
the pathogenesis of AD. It states that an
imbalance exists between the production
and clearance of â-amyloid peptide
(a peptide produced during normal cell
metabolism) in the brain.3 The accumulation
of â-amyloid peptide causes
damage to the neurons through multiple
mechanisms including inflammation,
production of neuritic plaques and
neurofibrillary tangles, and neuron toxicity
due to excessive stimulation of the
N-methyl-D-aspartate (NMDA) receptor
by glutamate. Damage to neurons leads
to the depletion of neurotransmitters,
such as acetylcholine, norepinephrine,
and serotonin, causing the clinical manifestations
of AD.4

AD currently has no cure, and pharmacologic
therapy focuses on regulation
of neurotransmittors, not on halting or
preventing the underlying cause of the
disease. Therefore, nonpharmacologic
behavioral interventions are the mainstay
of therapy for patients and families
living with AD. Behavioral modification,
simplification of demands and tasks,
increased physical activity, and education
and counseling for family members
are important components of a multidisciplinary
approach to caring for the AD
patient. Pharmacologic interventions
can help to slow the progression of the
disease, reduce symptoms, and improve
quality of life. Both therapeutic modalities
are often used in conjunction with
each other because of the profound
effects of AD on the patient as well as
family members and caregivers.

Counseling the Caregiver

Because nonpharmacologic treatments
are the mainstay of caring for the patient
with AD, the pharmacist plays a pivotal
role in reinforcing important counseling
points with family members and caregivers.
Education for the AD patient's
caregiver has shown to improve caregiver
satisfaction, knowledge, and confidence. It also has been known to potentially
delay nursing home placement,
although it has no effect on disease
severity or patient outcome.5

Behavioral modification strategies,
including limiting wardrobe choices
and accessories, encouraging showering
instead of bathing because of ease,
and eliminating unnecessary furniture
that could pose an environmental hazard
and increase the patient's risk of
fall, are important interventions to minimize
harm to the patient. Confrontation
and aggression can often be avoided by
simplifying tasks and demands. Brain
exercises and increasing physical activity
may increase cerebral blood flow
and oxygen consumption, resulting in
improvements in cognition. Ultimately,
the caregiver should be reminded that
sudden declines in mentation should
be referred to a health care provider for
management.

Summary of Pharmacologic Agents Used in the Treatment of Alzheimer's Disease

Agent

Dosage Forms Available

Starting Dose and Schedule

Effective Daily Dose

Titration

Donepezil (Aricept; Aricept ODT)

Tablets; ODT

5-10 mg once daily in the evening with or without food

5-10 mg

5 mg over 4-6 weeks

Galantamine (Razadyne; Razadyne ER)

Tablets and oral solution (immediate release); capsules (ER)

4 mg twice a day with food (immediate release); 8 mg once daily in the morning, preferably with food (ER)

Medications to Slow Disease
Progression

The American College of Physicians
and the American Academy of Family
Physicians recently published a clinical
practice guideline with recommendations
for pharmacologic treatment in the
AD patient. The document emphasizes
an individualized approach to choosing
to initiate pharmacologic therapy, based
on evaluating the patient's benefits and
risks of treatment. Further, because of
limited clinical trial evidence comparing
the efficacy of available therapeutic
agents, drug therapy selection should
be based on ease of use, adverse effect
profile, patient tolerability, and cost of
medication.6

Cholinesterase Inhibitors

For patients with mild-to-moderate AD,
cholinesterase inhibitors are the agents
with the strongest evidence of efficacy
in treating cognitive symptoms, according
to the American Association for
Geriatric Psychiatry.7 Because a primary
pathology of AD is a deficiency in acetylcholine,
agents in this category exert
their pharmacologic effect by inhibiting
the enzyme acetylcholinesterase, reducing
the hydrolysis of acetylcholine and
subsequently increasing levels of acetylcholine
available in the synaptic space.
Four agents in this category have been
approved by the FDA: tacrine (Cognex),
donepezil (Aricept), rivastigmine (Exelon),
and galantamine (Razadyne). No
strong clinical evidence exists indicating
that one agent is superior in efficacy
to another. Due to complex dosing and
safety concerns, however-specifically
the risk of causing hepatoxicity-
tacrine is generally not recommended
for routine use.

Other common side effects associated
with all of these agents are significant
gastrointestinal adverse reactions,
including nausea, vomiting, anorexia,
and weight loss. To minimize the risk of
these unwanted side effects, common
strategies include starting with the lowest
doses, using a slow titration schedule,
using alternative dosage forms (ie,
transdermal patch), and taking medications
with food. Refer to the Table for a
comparison of available dosage forms,
dosing, and titration schedules for the
various agents.

NMDA Antagonist

Memantine (Namenda) is currently the
only available NMDA antagonist approved
for the treatment of moderateto-
severe AD. Memantine is thought to
exert its pharmacologic effect by binding
to glutamate receptors to attenuate
glutaminergic excitotoxicity and provide
symptomatic improvements in memory
and daily function. Memantine dosing
information can be found in the Table.
Memantine is generally well tolerated,
although common side effects include
dizziness, headache, hallucinations, confusion,
and constipation. Because memantine
is not hepatically metabolized, it is
unlikely to be associated with significant
hepatic drug–drug interactions. Still, caution
should be taken with concomitant
administration of other medications likely
to have an effect at the NMDA receptor,
such as dextromethorphan.

Memantine can be used as monotherapy,
or in combination with the
cholinesterase inhibitors, to slow the
progression of AD. Results of clinical trials
in patients with moderate-to-severe
AD have shown the combination of
memantine plus cholinesterase inhibitor
may have a modest effect on improving
cognition, slowing the decline in activities
of daily living, and reducing the
frequency of the development of new
behavioral symptoms when compared
with placebo.8 The decision to combine
agents of these 2 classes should be
patient specific.

Medications to Control Behavioral
Symptoms

Behavioral symptoms, including depression,
social withdrawal, and mood
change, occur early in the course of
AD, whereas agitation, irritability, and
anxiety become more pronounced as
the disease progresses.9 Atypical antipsychotics
such as olanzapine (Zyprexa)
and risperidone (Risperdal) have
shown comparable efficacy in treating
behavioral symptoms in patients
with AD.10 These agents are preferred
over conventional antipsychotics due
to a lower risk of extrapyramidal side
effects.4 Approximately
20% of patients
receiving olanzapine and risperidone
discontinued treatment, because of
adverse effects, including sedation and
extrapyramidal side effects, which may
offset any benefit of these medications.
10 In addition, current atypical antipsychotics
have a black box warning
advising against using in patients with
dementia-related psychosis because of a
potential increased risk of death.11-13

It is important that health care professionals
carefully evaluate the risks and
benefits associated with using antipsychotic
medications in managing patients
with AD. Carbamazepine (Tegretol) and
valproic acid (Depakote) also may be
useful in managing behavioral symptoms.
4

Selective serotonin reuptake inhibitors
are preferred for the management
of depression in patients with AD.
Tricyclic antidepressants have significant
anticholinergic
adverse effects and
should be avoided.9 Short-acting benzodiazepines
can be useful for managing
nonpsychosis-related agitation in patients
with AD; however, long-term use
should be avoided due to the potential
for sedation and impaired cognition.9

Conclusion

AD is a growing public health concern.
Pharmacists can play an active role in
counseling patients and caregivers on
realistic outcome expectations, medication
costs, and potential adverse effects
from both pharmacologic and nonpharmacologic
therapies. Pharmacists also
can proactively identify concomitant
medications that may affect cognitive
function, such as sedatives and medications
with anticholinergic adverse
effects, as well as recommend alternative
therapies.

Qaseem A, Snow V, Cross JT, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148(5):370-378.

American Association for Geriatric Psychiatry Web site. AAGP Position Statement: Principles of Care for Patients With Dementia Resulting From Alzheimer Disease. www.aagponline.org/prof/position_caredmnalz.asp. Accessed December 17, 2008.